WO1997024123A1 - Utilisation d'un antagoniste du site de polyamine pour la fabrication d'un medicament destine au traitement de maladies ischemiques oculaires - Google Patents

Utilisation d'un antagoniste du site de polyamine pour la fabrication d'un medicament destine au traitement de maladies ischemiques oculaires Download PDF

Info

Publication number
WO1997024123A1
WO1997024123A1 PCT/EP1996/005671 EP9605671W WO9724123A1 WO 1997024123 A1 WO1997024123 A1 WO 1997024123A1 EP 9605671 W EP9605671 W EP 9605671W WO 9724123 A1 WO9724123 A1 WO 9724123A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
hydrogen atom
alkyl group
polyamine site
Prior art date
Application number
PCT/EP1996/005671
Other languages
English (en)
Inventor
Michael A. Kapin
Louis Desantis, Jr.
Bernard Scatton
Salomon Langer
Original Assignee
Synthelabo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthelabo filed Critical Synthelabo
Priority to AT96943986T priority Critical patent/ATE214605T1/de
Priority to JP9524002A priority patent/JP2000507205A/ja
Priority to DK96943986T priority patent/DK0871446T3/da
Priority to EP96943986A priority patent/EP0871446B1/fr
Priority to AU13739/97A priority patent/AU716670B2/en
Priority to DE69620027T priority patent/DE69620027T2/de
Publication of WO1997024123A1 publication Critical patent/WO1997024123A1/fr
Priority to HK99101082A priority patent/HK1016068A1/xx

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention rciaies generally to the field of ophthalmology.
  • the invention relates to the use of eiiprodil and related agents that prevent or attcmfflrr ischemic mediated neuronal injury and hence are useful for treating ischemia or hypoxia of the retina or optic nerve head in mammalian subjects.
  • giutamate is the major excitatory neurotrarismitter in the retina as well as most other regions in the central nervous system (Massey, S.. ''Cell types using giutamate as a neuro ⁇ ansinrtter in the verebrate retina, " ' Progress in Retina Research, Volume 9, edited by N. N. Osbome and G. J. Chader, Oxford: Pergammon Press, 399-425, 1990; Miller, R. F. and M. M.
  • EAA stimulation can result in neuronal injury (Olney, J. W., "Inciting excitotoxic cytocide among central neurons.” Adv. Exp. Med Biol. 203:631-645. 1986).
  • the process of excitotoxicity has been extensively studied in the retina.
  • Such toxicity to the inner retina has been observed following travitreal injection of EAAs, following application of EAAs to the isolated animal retina, or from exogenousiy applied giutamate to retinal ganglion cells in culture. See generally, SattayasaL et al.. "Morphology of qiiisquaiate-induced neurotoxicity in the chicken retina," Invest. Ophthdmol. Vis.
  • EAA receptors have been characterized as n ⁇ tabonopic or i ⁇ rr ⁇ tropic. Activation of a metabotropic receptor affects cellular processes via G-proteins; whereas ionotropic receptors affect the translocation of mono- and divalent cations across the cell iiiembraue. There are at least three ionotropic receptors that have been named for the agonist that preferentially stimulates the receptor. These receptors have been classified as: N-rnethyl-D-aspartate
  • EAA acetylcholine
  • srxrific ceils in the retina.
  • Cell types using giutamate as a neMUUansiu ter in the vertebrate retina See, for example, Massey. S., "Cell types using giutamate as a neMUUansiu ter in the vertebrate retina.
  • the present invention is directed to methods for treating ischemic di ⁇ with polyamine site antagonists.
  • Figure 1 shows the effect of euprodil on the restoration of the dectroretinogram following ischemic challenge in the pigmented rabbit
  • Polyamine site antagonists are useful in treating ischemic disorders of the mammalian, particulariy human, retina (e.g. branch and central veinartery occlusion) or optic nerve head (e.g. anterior ischemic optic neuropathy).
  • retina e.g. branch and central veinartery occlusion
  • optic nerve head e.g. anterior ischemic optic neuropathy
  • polyamine site antagonists such as eliprodiL partition across the blood-brain barrier and produce their actions at a modulatory site without side-effects typical of non- ⁇ ir ⁇ petitive antagonists.
  • Particulariy preferred polyamine site antagonists are certain l-phenyl-2-piperi ⁇ ino- alkanol derivatives of formula (I), below:
  • R lepichcms a hydrogen atom, a halogen atom, a uifluc ⁇ o ⁇ nethyl group, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, an alkanoyloxy group having from 1 to 16 carbon atoms or a benzoyloxy group, or, when R 2 ic ⁇ eseui a hydroxyl or methoxy group in the 4-position and R j le ⁇ ies ⁇ us a hydrogen atom, R ⁇ may also represent a hydroxymethyl group, a carbamoyl group or an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy part R 2 lepies ⁇ its a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group or an alkoxy group having from 1 to 4 carbon atoms, R,
  • the most preferred ⁇ mpounds are: 2-[4-(4-fluorobenzyl) ipcridino]- l-(4-chlorophenyl ethanol, also known as eiiprodil; 2-(4-be ⁇ zylpiperidino l- (4-hydroxyphenyl)-propanoL also known as ifenprodil; or a pharrnaceuticaily acceptable salt thereof.
  • the polyamine site antagonists useful in the present invention will be administered orally.
  • Daily dosage of these ⁇ mpounds will range between about 0.1 and about 500 milligrams (mg), preferably between about 5 and about 100 mg.
  • Local administration of these ⁇ mpou ⁇ ds will range between about 0.1 and about 500 mg, preferably between about 5 and about 100 mg.
  • An aqueous ⁇ mposition will generally contain between about 0.1 and about 10 percent by weight (wt%) of the active, preferably between about 1 and about 5 wt%.
  • SUBSTITUTE SHEET (RULE 26J elevating intraocular pressure above systemic blood pressure for 65 minutes.
  • all rabbits were put into a surgical plane of anesthesia by administering sodium pen ⁇ barbital. Ischemia was con ⁇ rmed by a cessation of A and B wave activity ( ⁇ 15 ( ⁇ V).
  • rabbits were adrm concludedred i ⁇ rravenously 3 mgkg of EliprodiL 10 mgl ⁇ EliprodU was giv ⁇ intn ⁇ eritoneaU 12, 24 and 36 hours following the ischemic period ERG recordings were made prior to ischemia and at 24 and 48 hours post-ischemia.
  • Panel A shows the effect of Eiiprodil on B wave amplitude ⁇ mpared to vehicle Heated animals.
  • B wave amplitude is thought to be a composite of Mulle s cell and Bipolar cell activity.
  • Drug treatment resulted in a 70.7% and 77.9% increase (p ⁇ .05) over vehicle treated amplitudes at 24 and 48 hours post ischemia, respectively.
  • panel B the functionality of the outer retina was evaluated through measurement of A wave amplitude. The 24 hour increase in A wave amplitude by Eiiprodil treated rabbits (109% increase above vehicle) was proportionally greater than that seen in the B wave amplitude at this period

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'antagonistes du site de polyamine dans le traitement de maladies ischémiques de la rétine et de la tête du nerf optique. Particulièrement préférés sont certains dérivés de 1-phényle-2-pipéridinoalcanol, tels qu'eliprodil et ifenprodil.
PCT/EP1996/005671 1996-01-02 1996-12-17 Utilisation d'un antagoniste du site de polyamine pour la fabrication d'un medicament destine au traitement de maladies ischemiques oculaires WO1997024123A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AT96943986T ATE214605T1 (de) 1996-01-02 1996-12-17 Verwendung von eliprodil zur herstellung eines arzneimittels zur behandlung von ischämischen störungen der retina oder des sehnervs
JP9524002A JP2000507205A (ja) 1996-01-02 1996-12-17 眼の虚血障害の治療薬の製造のためのポリアミン部位拮抗物質の使用
DK96943986T DK0871446T3 (da) 1996-01-02 1996-12-17 Anvendelse af eliprodil til fremstilling af et lægemiddel til behandling af ischaemiske sygdomme i nethinden eller den optiske nerve
EP96943986A EP0871446B1 (fr) 1996-01-02 1996-12-17 Utilisation d'eliprofil pour la fabrication d'un medicament destine au traitement de maladies ischemiques de la retine ou du nerf optique
AU13739/97A AU716670B2 (en) 1996-01-02 1996-12-17 Use of polyamine site antagonist for the manufacture of a medicament for the treatment of ischemic disorders of the eye
DE69620027T DE69620027T2 (de) 1996-01-02 1996-12-17 Verwendung von eliprodil zur herstellung eines arzneimittels zur behandlung von ischämischen störungen der retina oder des sehnervs
HK99101082A HK1016068A1 (en) 1996-01-02 1999-03-16 Use of eliprodil for the manufacture of a medicament for the treatment of ischemic disorders of the retina of the optic nerve

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US58200396A 1996-01-02 1996-01-02
US08/582,003 1996-01-02

Publications (1)

Publication Number Publication Date
WO1997024123A1 true WO1997024123A1 (fr) 1997-07-10

Family

ID=24327451

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/005671 WO1997024123A1 (fr) 1996-01-02 1996-12-17 Utilisation d'un antagoniste du site de polyamine pour la fabrication d'un medicament destine au traitement de maladies ischemiques oculaires

Country Status (12)

Country Link
US (1) US6020352A (fr)
EP (1) EP0871446B1 (fr)
JP (1) JP2000507205A (fr)
AT (1) ATE214605T1 (fr)
AU (1) AU716670B2 (fr)
CA (1) CA2241913A1 (fr)
DE (1) DE69620027T2 (fr)
DK (1) DK0871446T3 (fr)
ES (1) ES2171233T3 (fr)
HK (1) HK1016068A1 (fr)
PT (1) PT871446E (fr)
WO (1) WO1997024123A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014205A1 (fr) 1996-09-30 1998-04-09 David John Maudsley Therapie anticancereuse faisant appel a un produit oncogene et a une molecule etrangere du complexe majeur d'histocompatibilite
EP1126850A1 (fr) * 1998-10-27 2001-08-29 Alcon Laboratories, Inc. Traitement des affections de la retine
GB2432526A (en) * 2005-11-24 2007-05-30 Arakis Ltd Use of ifenprodil for the treatment of ophthalmic diseases

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030212107A1 (en) * 2001-05-10 2003-11-13 Kapin Michael A. R-reliprodil for treating glaucoma
CA2556589A1 (fr) * 2004-02-24 2005-09-01 Bioaxone Therapeutique Inc. Derives de piperidine substitues en position 4
US10106525B2 (en) 2015-01-26 2018-10-23 BioAxone BioSciences, Inc. Rho kinase inhibitor BA-1049 (R) and active metabolites thereof
US10857157B2 (en) 2015-01-26 2020-12-08 BioAxone BioSciences, Inc. Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors
US10149856B2 (en) 2015-01-26 2018-12-11 BioAxone BioSciences, Inc. Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors
US11198680B2 (en) 2016-12-21 2021-12-14 BioAxone BioSciences, Inc. Rho kinase inhibitor BA-1049 (R) and active metabolites thereof
WO2019014322A1 (fr) 2017-07-11 2019-01-17 BioAxone BioSciences, Inc. Inhibiteurs de kinase pour le traitement de maladies

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690931A (en) * 1982-10-13 1987-09-01 Synthelabo Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives
WO1994013275A1 (fr) * 1992-12-04 1994-06-23 Massachusetts Eye And Ear Infirmary Traitement du glaucome

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690931A (en) * 1982-10-13 1987-09-01 Synthelabo Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives
WO1994013275A1 (fr) * 1992-12-04 1994-06-23 Massachusetts Eye And Ear Infirmary Traitement du glaucome

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
G.CORNAND ET AL.: "Notre expérience du tartrate d'ifenprodil (Validex) en ophthalmologie", MEDITERR. MED., vol. 7, no. 191, 2 May 1979 (1979-05-02), pages 105 - 107, XP002030516 *
G.ZEEVALK ET AL.: "Action of the anti-ischemic agent ifenprodil on N-methyl-D-aspartate and kainate-mediated excitotoxicity", BRAIN RES., vol. 522, no. 1, 1990, pages 135 - 139, XP000653449 *
M.KAPIN ET AL.: "Protective effect of the polyamine antagonist, eliprodil hydrochloride in retina sujected to an excitotoxic- or ischemic insult", SOC.NEURISCI.ABSTR., vol. 22, no. 1-3, 1996, pages 1279, XP000653689 *
R.CRAMPINCHI ET AL.: "Traitement par injections rétrobulbaires répétées de vasodilatateurs des névrites optiques alcoolo-nicotiniques", BULL. MEM. SOC.FR. OPHTHALM., vol. 89, 1977, pages 339 - 341, XP000653394 *
R.MORGAN: "Open-angle glaucoma: An epidemiologist's view", CAN. J. OPHTHALMOL, vol. 7, no. 1, 1972, pages 75 - 79, XP000653413 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014205A1 (fr) 1996-09-30 1998-04-09 David John Maudsley Therapie anticancereuse faisant appel a un produit oncogene et a une molecule etrangere du complexe majeur d'histocompatibilite
EP1126850A1 (fr) * 1998-10-27 2001-08-29 Alcon Laboratories, Inc. Traitement des affections de la retine
EP1126850A4 (fr) * 1998-10-27 2003-01-15 Alcon Lab Inc Traitement des affections de la retine
GB2432526A (en) * 2005-11-24 2007-05-30 Arakis Ltd Use of ifenprodil for the treatment of ophthalmic diseases

Also Published As

Publication number Publication date
HK1016068A1 (en) 1999-10-29
ES2171233T3 (es) 2002-09-01
DE69620027D1 (de) 2002-04-25
PT871446E (pt) 2002-08-30
DE69620027T2 (de) 2002-09-05
CA2241913A1 (fr) 1997-07-10
DK0871446T3 (da) 2002-04-15
EP0871446B1 (fr) 2002-03-20
AU716670B2 (en) 2000-03-02
US6020352A (en) 2000-02-01
ATE214605T1 (de) 2002-04-15
JP2000507205A (ja) 2000-06-13
AU1373997A (en) 1997-07-28
EP0871446A1 (fr) 1998-10-21

Similar Documents

Publication Publication Date Title
US5710165A (en) Use of polyamine antagonists for the treatment of glaucoma
US6277855B1 (en) Method of treating dry eye disease with nicotinic acetylcholine receptor agonists
EP2156833B1 (fr) Agent prophylactique ou thérapeutique destiné à une maladie oculaire postérieure comprenant un agoniste qui n'est pas dérivé de l'ergot de seigle sélectif du récepteur d2 en tant que principe actif
AU2269983A (en) Composition and method for treatment of glaucoma
KR20020082885A (ko) 외망막의 질환을 치료하기에 유용한 ５－ｈｔ１ａ 활성을가진 화합물
WO2005030221A1 (fr) Agent therapeutique contre la degenerescence maculaire liee a l'age
US20020161013A1 (en) Method of local anesthesia and analgesia
WO1989010757A1 (fr) Nouvelle preparation ophtalmique pour le traitement de glaucomes
AU704938B2 (en) Combination therapy for treating glaucoma
WO1997024123A1 (fr) Utilisation d'un antagoniste du site de polyamine pour la fabrication d'un medicament destine au traitement de maladies ischemiques oculaires
IE913137A1 (en) Method of treating ocular pain
CN108289901A (zh) 用于预防和治疗眼痛的氨基次膦酸衍生物
JPH08511024A (ja) 眼内圧を低下させる方法および組成物
US5266580A (en) Treatment of low pressure glaucoma and ischemic retinal degeneration with droperidol
US5153205A (en) Method to reduce introacular pressure without causing miosis
US5252607A (en) Treatment of low pressure glaucoma and ischemic retinal degeneration
AU716577B2 (en) Use of polyamine antagonists for the treatment of glaucoma
WO1995031200A1 (fr) Composition pharmaceutique contenant de la terazosine, pour le traitment du glaucome
AU644679B2 (en) Composition for treating ocular pain
JPH11508879A (ja) 緑内障治療のためのポリアミン拮抗剤の使用
US20150273011A1 (en) Topical corneal analgesia using neurotensin receptor agonists and synergistic neurotensin combinations without delaying wound healing

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP MX

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996943986

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2241913

Country of ref document: CA

Ref document number: 2241913

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/A/1998/005382

Country of ref document: MX

WWP Wipo information: published in national office

Ref document number: 1996943986

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1996943986

Country of ref document: EP